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Cerebral small vessel disease genomics and its implications across the lifespan

Author

Listed:
  • Muralidharan Sargurupremraj

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Hideaki Suzuki

    (Tohoku University, 2-1, Seiryo, Aoba
    Tohoku University Hospital, 1-1, Seiryo, Aoba
    Imperial College London)

  • Xueqiu Jian

    (University of Texas Health Science Center at Houston McGovern Medical School
    University of Texas Health Sciences Center)

  • Chloé Sarnowski

    (Boston University School of Public Health)

  • Tavia E. Evans

    (Erasmus MC
    Erasmus MC)

  • Joshua C. Bis

    (University of Washington)

  • Gudny Eiriksdottir

    (Icelandic Heart Association)

  • Saori Sakaue

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences, Tsurumi-ku
    Graduate School of Medicine, the University of Tokyo)

  • Natalie Terzikhan

    (Erasmus MC)

  • Mohamad Habes

    (University of Texas Health Sciences Center
    University of Pennsylvania
    University Medicine Greifswald)

  • Wei Zhao

    (School of Public Health, University of Michigan)

  • Nicola J. Armstrong

    (Murdoch University)

  • Edith Hofer

    (Medical University of Graz
    Medical University of Graz)

  • Lisa R. Yanek

    (Johns Hopkins University School of Medicine)

  • Saskia P. Hagenaars

    (University of Edinburgh
    Psychology & Neuroscience, King’s College London)

  • Rajan B. Kumar

    (University of California at Davis)

  • Erik B. Akker

    (Leiden university Medical Center
    Delft University of Technology
    Leiden University Medical Centre)

  • Rebekah E. McWhirter

    (University of Tasmania
    University of Tasmania)

  • Stella Trompet

    (Leiden University Medical Center
    Leiden University Medical Center)

  • Aniket Mishra

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Yasaman Saba

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center
    Medical University of Graz)

  • Claudia L. Satizabal

    (University of Texas Health Sciences Center
    Boston University and the NHLBI’s Framingham Heart Study
    Boston University School of Medicine)

  • Gregory Beaudet

    (University of Bordeaux, IMN)

  • Laurent Petit

    (University of Bordeaux, IMN)

  • Ami Tsuchida

    (University of Bordeaux, IMN)

  • Laure Zago

    (University of Bordeaux, IMN)

  • Sabrina Schilling

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Sigurdur Sigurdsson

    (Icelandic Heart Association)

  • Rebecca F. Gottesman

    (Johns Hopkins University School of Medicine)

  • Cora E. Lewis

    (University of Alabama at Birmingham School of Medicine)

  • Neelum T. Aggarwal

    (Rush University Medical Center)

  • Oscar L. Lopez

    (University of Pittsburgh)

  • Jennifer A. Smith

    (School of Public Health, University of Michigan
    University of Michigan)

  • Maria C. Valdés Hernández

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh)

  • Jeroen Grond

    (Leiden University medical Center)

  • Margaret J. Wright

    (The University of Queensland
    The University of Queensland)

  • Maria J. Knol

    (Erasmus MC)

  • Marcus Dörr

    (University Medicine Greifswald
    DZHK (German Center for Cardiovascular Research), partner site Greifswald)

  • Russell J. Thomson

    (University of Tasmania
    Western Sydney University)

  • Constance Bordes

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Quentin Grand

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Marie-Gabrielle Duperron

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Albert V. Smith

    (Icelandic Heart Association)

  • David S. Knopman

    (Mayo Clinic)

  • Pamela J. Schreiner

    (University of Minnesota School of Public Health)

  • Denis A. Evans

    (Rush University Medical Center)

  • Jerome I. Rotter

    (Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center)

  • Alexa S. Beiser

    (Boston University School of Public Health
    Boston University and the NHLBI’s Framingham Heart Study
    Boston University School of Medicine)

  • Susana Muñoz Maniega

    (University of Edinburgh
    University of Edinburgh)

  • Marian Beekman

    (Leiden university Medical Center)

  • Julian Trollor

    (University of New South Wales
    University of New South Wales)

  • David J. Stott

    (Veterinary and Life Sciences, University of Glasgow)

  • Meike W. Vernooij

    (Erasmus MC
    Erasmus MC)

  • Katharina Wittfeld

    (German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald)

  • Wiro J. Niessen

    (Erasmus MC
    Delft University of Technology)

  • Aicha Soumaré

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Eric Boerwinkle

    (University of Texas Health Science Center at Houston School of Public Health)

  • Stephen Sidney

    (Kaiser Permanente Division of Research)

  • Stephen T. Turner

    (Division of Nephrology and Hypertension, Mayo Clinic)

  • Gail Davies

    (Medical University of Graz
    University of Edinburgh)

  • Anbupalam Thalamuthu

    (Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center)

  • Uwe Völker

    (University Medicine Greifswald)

  • Mark A. Buchem

    (University of Edinburgh)

  • R. Nick Bryan

    (The University of Texas at Austin Dell Medical School)

  • Josée Dupuis

    (University of Texas Health Sciences Center
    Leiden University Medical Center)

  • Mark E. Bastin

    (Medical University of Graz
    University of Michigan)

  • David Ames

    (National Ageing Research Institute Royal Melbourne Hospital
    University of Melbourne, St George’s Hospital)

  • Alexander Teumer

    (Erasmus MC
    University Medicine Greifswald)

  • Philippe Amouyel

    (Inserm U1167
    Pasteur Institute of Lille)

  • John B. Kwok

    (Brain and Mind Centre - The University of Sydney
    University of New South Wales)

  • Robin Bülow

    (University Medicine Greifswald)

  • Ian J. Deary

    (Medical University of Graz
    University of Edinburgh)

  • Peter R. Schofield

    (University of New South Wales
    Neuroscience Research Australia)

  • Henry Brodaty

    (Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
    University of New South Wales)

  • Jiyang Jiang

    (Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center)

  • Yasuharu Tabara

    (Kyoto University Graduate School of Medicine)

  • Kazuya Setoh

    (Kyoto University Graduate School of Medicine)

  • Susumu Miyamoto

    (Kyoto University Graduate School of Medicine)

  • Kazumichi Yoshida

    (Kyoto University Graduate School of Medicine)

  • Manabu Nagata

    (Kyoto University Graduate School of Medicine)

  • Yoichiro Kamatani

    (Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku)

  • Fumihiko Matsuda

    (Kyoto University Graduate School of Medicine)

  • Bruce M. Psaty

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • David A. Bennett

    (Rush University Medical Center)

  • Philip L. Jager

    (Columbia University Medical Center
    Broad Institute of MIT and Harvard)

  • Thomas H. Mosley

    (University of Mississippi Medical Center)

  • Perminder S. Sachdev

    (Los Angeles Biomedical Research Institute and Pediatrics at Harbor-UCLA Medical Center
    Neuropsychiatric Institute, Prince of Wales Hospital)

  • Reinhold Schmidt

    (School of Public Health, University of Michigan)

  • Helen R. Warren

    (Queen Mary University of London
    Queen Mary University of London)

  • Evangelos Evangelou

    (School of Public Health, Imperial College London
    University of Ioannina Medical School)

  • David-Alexandre Trégouët

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center)

  • Mohammad A. Ikram

    (Erasmus MC)

  • Wei Wen

    (University of New South Wales)

  • Charles DeCarli

    (University of California at Davis)

  • Velandai K. Srikanth

    (University of Tasmania
    Monash University)

  • J. Wouter Jukema

    (Leiden University Medical Center)

  • Eline P. Slagboom

    (Leiden university Medical Center)

  • Sharon L. R. Kardia

    (School of Public Health, University of Michigan)

  • Yukinori Okada

    (Osaka University Graduate School of Medicine
    RIKEN Center for Integrative Medical Sciences, Tsurumi-ku
    Osaka University)

  • Bernard Mazoyer

    (University of Bordeaux, IMN)

  • Joanna M. Wardlaw

    (University of Edinburgh
    University of Edinburgh
    University of Edinburgh
    MRC UK Dementia Research Institute at the University of Edinburgh)

  • Paul A. Nyquist

    (Johns Hopkins School of Medicine
    Johns Hopkins School of Medicine)

  • Karen A. Mather

    (University of New South Wales
    Neuroscience Research Australia)

  • Hans J. Grabe

    (University Medicine Greifswald
    German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald)

  • Helena Schmidt

    (Medical University of Graz)

  • Cornelia M. Duijn

    (University of Oxford)

  • Vilmundur Gudnason

    (Icelandic Heart Association
    University of Iceland, Faculty of Medicine)

  • William T. Longstreth

    (University of Washington)

  • Lenore J. Launer

    (The National Institutes of Health
    Intramural Research Program/National Institute on Aging/National Institutes of Health)

  • Mark Lathrop

    (University of McGill Genome Center)

  • Sudha Seshadri

    (University of Texas Health Sciences Center
    Boston University and the NHLBI’s Framingham Heart Study
    Boston University School of Medicine)

  • Christophe Tzourio

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center
    Service d’information médicale)

  • Hieab H. Adams

    (Erasmus MC
    Erasmus MC)

  • Paul M. Matthews

    (Imperial College London
    UK Dementia Research Institute
    Imperial College London)

  • Myriam Fornage

    (University of Texas Health Science Center at Houston McGovern Medical School)

  • Stéphanie Debette

    (University of Bordeaux, Inserm, Bordeaux Population Health Research Center
    Boston University School of Medicine
    Department of Neurology, CHU de Bordeaux)

Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Suggested Citation

  • Muralidharan Sargurupremraj & Hideaki Suzuki & Xueqiu Jian & Chloé Sarnowski & Tavia E. Evans & Joshua C. Bis & Gudny Eiriksdottir & Saori Sakaue & Natalie Terzikhan & Mohamad Habes & Wei Zhao & Nicol, 2020. "Cerebral small vessel disease genomics and its implications across the lifespan," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19111-2
    DOI: 10.1038/s41467-020-19111-2
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    Cited by:

    1. Zhijian Yang & Junhao Wen & Ahmed Abdulkadir & Yuhan Cui & Guray Erus & Elizabeth Mamourian & Randa Melhem & Dhivya Srinivasan & Sindhuja T. Govindarajan & Jiong Chen & Mohamad Habes & Colin L. Master, 2024. "Gene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Catherine M. Francis & Matthias E. Futschik & Jian Huang & Wenjia Bai & Muralidharan Sargurupremraj & Alexander Teumer & Monique M. B. Breteler & Enrico Petretto & Amanda S. R. Ho & Philippe Amouyel &, 2022. "Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Yash Patel & Jean Shin & Eeva Sliz & Ariana Tang & Aniket Mishra & Rui Xia & Edith Hofer & Hema Sekhar Reddy Rajula & Ruiqi Wang & Frauke Beyer & Katrin Horn & Max Riedl & Jing Yu & Henry Völzke & Rob, 2024. "Genetic risk factors underlying white matter hyperintensities and cortical atrophy," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Stergios Tsartsalis & Hannah Sleven & Nurun Fancy & Frank Wessely & Amy M. Smith & Nanet Willumsen & To Ka Dorcas Cheung & Michal J. Rokicki & Vicky Chau & Eseoghene Ifie & Combiz Khozoie & Olaf Ansor, 2024. "A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Thomas S. Wingo & Yue Liu & Ekaterina S. Gerasimov & Selina M. Vattathil & Meghan E. Wynne & Jiaqi Liu & Adriana Lori & Victor Faundez & David A. Bennett & Nicholas T. Seyfried & Allan I. Levey & Aliz, 2022. "Shared mechanisms across the major psychiatric and neurodegenerative diseases," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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